Over 150 million people are infected with Hepatitis C Virus (HCV) worldwide. Unfortunately, many of these individuals are unable to clear their infection with the current standard of care, which consists of treatment with a combination of interferon and ribavirin. Moreover, this treatment is associated with significant side effects, precluding its use by many individuals. Thus, current therapies are inadequate for the majority of the patients, and there is a pressing need for new drugs to treat HCV infection (See, Annals Internal Med. 132:296).
The 9.6-kb positive single-stranded RNA HCV genome encodes a 3,000-amino-acid polyprotein which is proteolytically processed into structural proteins, which are components of the mature virus, and nonstructural proteins (NS), which are involved in replicating the viral genome (Curr Top Microbiol Immunol 242, 55-84 (2000)). Like other positive strand RNA viruses (B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology. (Lippincott-Raven Publications, Philadelphia, Pa., 1996, in “The viruses and their replication”)), HCV appears to replicate in association with intracellular membrane structures. In the case of HCV, the structures are termed the membranous web (J Virol 76, 5974-5984 (2002)) and are believed to be induced by the NS4B protein. NS4B is also required to assemble the other viral NS proteins within the apparent sites of RNA replication (J Virol 78, 11393-11400 (2004)). It is not known how viral RNA, especially the negative strand template required for production of progeny genomes, might be incorporated or maintained at these replication sites.
There is an ongoing need in the art for agents that treat HCV infection; and for methods of identifying candidate agents that are suitable for treating HCV infection.